CAMBRIDGE, Mass. (Business Wire) -- Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today positive top-line results from its ongoing
Phase I trial of ALN-TTRsc, a subcutaneously administered RNAi
therapeutic targeting the transthyretin (TTR) gene for the treatment of
TTR-mediated amyloidosis (ATTR). The company is reporting that ALN-TTRsc
achieved robust and statistically significant (p<0.01) knockdown of
serum TTR protein levels of greater than 80% in healthy volunteer
subjects, in line with results for ALN-TTRsc previously reported in
non-human primates. In addition, to date ALN-TTRsc was found to be
generally safe and well tolerated. Dose escalation in this trial
continues and results will be presented at the Annual Scientific Meeting
of the Heart Failure Society of America (HFSA), being held September 22
– 25, 2013 in Orlando, Fla. These human study results are the first to
be reported for Alnylam's proprietary GalNAc-siRNA conjugate delivery
platform, enabling subcutaneous dosing of RNAi therapeutics with a wide
therapeutic index.

“These clinical results with ALN-TTRsc establish human translation for
RNAi therapeutics that utilize our GalNAc-siRNA conjugate delivery
platform. This platform enables subcutaneous dose administration with a
wide therapeutic index and has now become our primary approach for
development of RNAi therapeutics. As a result, we believe these data are
very meaningful not only for the continued advancement of ALN-TTRsc, but
also for the continued execution on our entire ‘Alnylam 5x15' product
strategy,” said John Maraganore, Ph.D., Chief Executive Officer of
Alnylam. “Specifically, we are very excited to report top-line results
from the study showing statistically significant knockdown of serum TTR
to levels greater than 80% in treated subjects, results which are in
line with our non-human primate experience. We look forward to continued
advancement of our ALN-TTRsc program, including presentation of data
from the Phase I trial at the HFSA meeting in September, start of a
Phase II study in familial amyloidotic cardiomyopathy patients by the
end of this year, and – assuming positive results – start of a pivotal
Phase III trial for ALN-TTRsc in 2014.”

ATTR is caused by mutations in the TTR gene which cause abnormal amyloid
protein deposits to accumulate in various tissues including peripheral
nerves and heart, resulting in neuropathy and/or cardiomyopathy. ATTR
represents a major unmet medical need with significant morbidity and
mortality; familial amyloidotic polyneuropathy (FAP) affects
approximately 10,000 people worldwide and familial amyloidotic
cardiomyopathy (FAC) affects at least 40,000 people worldwide.
ALN-TTRsc, which is being developed for the treatment of FAC, is a
subcutaneously administered RNAi therapeutic that comprises an siRNA
conjugated to a GalNAc ligand that enables receptor-mediated delivery to
the liver. ALN-TTRsc is the first GalNAc-siRNA – and the first
subcutaneously delivered – systemic RNAi therapeutic to enter clinical
development stages. Alnylam is also developing ALN-TTR02, an
intravenously administered RNAi therapeutic targeting TTR for the
treatment of FAP patients with ATTR.

The ongoing Phase I trial of ALN-TTRsc is being conducted in the U.K. as
a randomized, double-blind, placebo-controlled, single- and multi-dose,
dose-escalation study, enrolling up to 40 healthy volunteer subjects.
Subjects received single or multiple ascending subcutaneous doses of
ALN-TTRsc ranging from 1.25 to 10 mg/kg. The primary objective of the
study is to evaluate the safety and tolerability of single and multiple
doses of subcutaneously administered ALN-TTRsc. Secondary objectives
include assessment of clinical activity of the drug as measured by serum
TTR levels. Upon completion of the Phase I trial, the company plans to
start a Phase II clinical study of ALN-TTRsc in FAC patients in late
2013 and, assuming positive results, expects to start a pivotal Phase
III trial for ALN-TTRsc in FAC patients in 2014.

Pre-clinical
studies have shown that subcutaneous administration of ALN-TTRsc
resulted in potent and sustained suppression of TTR. In non-human
primates, ALN-TTRsc administration resulted in an approximately 80%
reduction of TTR at doses as low as 2.5 mg/kg. In single- and multi-dose
pre-clinical safety studies in rodents and non-human primates, ALN-TTRsc
was found to be generally safe and well tolerated. Specifically, at
doses as high as 300 mg/kg in non-human primates, ALN-TTRsc was well
tolerated with no clinical signs, no adverse laboratory or
histopathologic findings, no elevations in cytokines or complement, and
no significant injection site reactions; these results demonstrate an
approximately 100-fold therapeutic index for GalNAc-siRNA conjugates.

In 2012, Alnylam entered into an exclusive alliance with Genzyme, a
Sanofi company, to develop and commercialize RNAi therapeutics,
including ALN-TTR02 and ALN-TTRsc, for the treatment of ATTR in Japan
and the broader Asian-Pacific region. Alnylam plans to develop and
commercialize the ALN-TTR program in North and South America, Europe,
and rest of the world.

Alnylam is hosting an R&D Day today from 8:30 a.m. – 12:00 p.m. ET at
the Sofitel New York in New York City. Alnylam scientists and management
will review progress with the company's “Alnylam 5×15” product strategy
for the development of RNAi therapeutics. The event will be webcast live
on the News & Investors section of the company's website, www.alnylam.com.
An audio replay of the event will be available on the Alnylam website
approximately 90 minutes after the event.

About Transthyretin-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited,
progressively debilitating, and fatal disease caused by mutations in the
TTR gene. TTR protein is produced primarily in the liver and is normally
a carrier for retinol binding protein. Mutations in TTR cause abnormal
amyloid proteins to accumulate and damage body organs and tissue, such
as the peripheral nerves and heart, resulting in intractable peripheral
sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy. ATTR
represents a major unmet medical need with significant morbidity and
mortality; familial amyloidotic polyneuropathy (FAP) affects
approximately 10,000 people worldwide and familial amyloidotic
cardiomyopathy (FAC) affects at least 40,000 people worldwide. FAP
patients have a life expectancy of five to 15 years from symptom onset,
and the only treatment options for early stage disease are liver
transplantation and tafamidis (approved in Europe). The mean survival
for FAC patients is approximately 2.5 years, and there are no approved
therapies. There is a significant need for novel therapeutics to treat
patients who have inherited mutations in the TTR gene.

About GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and
are designed to achieve targeted delivery of RNAi therapeutics to
hepatocytes through uptake by the asialoglycoprotein receptor. Research
findings demonstrate potent and durable target gene silencing, as well
as a wide therapeutic index, with subcutaneously administered
GalNAc-siRNAs from multiple “Alnylam 5x15” programs.

About RNA Interference (RNAi)

RNAi (RNA interference) is a revolution in biology, representing a
breakthrough in understanding how genes are turned on and off in cells,
and a completely new approach to drug discovery and development. Its
discovery has been heralded as “a major scientific breakthrough that
happens once every decade or so,” and represents one of the most
promising and rapidly advancing frontiers in biology and drug discovery
today which was awarded the 2006 Nobel Prize for Physiology or Medicine.
RNAi is a natural process of gene silencing that occurs in organisms
ranging from plants to mammals. By harnessing the natural biological
process of RNAi occurring in our cells, the creation of a major new
class of medicines, known as RNAi therapeutics, is on the horizon. Small
interfering RNA (siRNA), the molecules that mediate RNAi and comprise
Alnylam's RNAi therapeutic platform, target the cause of diseases by
potently silencing specific mRNAs, thereby preventing disease-causing
proteins from being made. RNAi therapeutics have the potential to treat
disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics
based on RNA interference, or RNAi. The company is leading the
translation of RNAi as a new class of innovative medicines with a core
focus on RNAi therapeutics toward genetically defined targets for the
treatment of serious, life-threatening diseases with limited treatment
options for patients and their caregivers. These include: ALN-TTR02, an
intravenously delivered RNAi therapeutic targeting transthyretin (TTR)
for the treatment of TTR-mediated amyloidosis (ATTR) in patients with
familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously
delivered RNAi therapeutic targeting TTR for the treatment of ATTR in
patients with familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an
RNAi therapeutic targeting antithrombin (AT) for the treatment of
hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi
therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the
treatment of acute intermittent porphyria (AIP); ALN-PCS, an RNAi
therapeutic targeting PCSK9 for the treatment of hypercholesterolemia;
ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of
beta-thalassemia and iron-overload disorders; ALN-AAT, an RNAi
therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT
deficiency liver disease; and ALN-CC5, an RNAi therapeutic targeting the
C5 component of the complement pathway for the treatment of
complement-mediated diseases, amongst other programs. As part of its
“Alnylam 5x15TM” strategy, the company expects to have five
RNAi therapeutic products for genetically defined diseases in clinical
development, including programs in advanced stages, on its own or with a
partner by the end of 2015. Alnylam has additional partnered programs in
clinical or development stages, including ALN-RSV01 for the treatment of
respiratory syncytial virus (RSV) infection and ALN-VSP for the
treatment of liver cancers. The company's leadership position on RNAi
therapeutics and intellectual property have enabled it to form major
alliances with leading companies including Merck, Medtronic, Novartis,
Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, Ascletis,
Monsanto, Genzyme, and The Medicines Company. In addition, Alnylam holds
an equity position in Regulus Therapeutics Inc., a company focused on
discovery, development, and commercialization of microRNA therapeutics.
Alnylam has also formed Alnylam Biotherapeutics, a division of the
company focused on the development of RNAi technologies for applications
in biologics manufacturing, including recombinant proteins and
monoclonal antibodies. Alnylam's VaxiRNA™ platform applies RNAi
technology to improve the manufacturing processes for vaccines;
GlaxoSmithKline is a collaborator in this effort. Alnylam scientists and
collaborators have published their research on RNAi therapeutics in over
100 peer-reviewed papers, including many in the world's top scientific
journals such as Nature, Nature Medicine, Nature
Biotechnology, and Cell. Founded in 2002, Alnylam maintains
headquarters in Cambridge, Massachusetts. For more information, please
visit www.alnylam.com.

About “Alnylam 5x15™”

The “Alnylam 5x15” strategy, launched in January 2011, establishes a
path for development and commercialization of novel RNAi therapeutics
toward genetically defined targets for the treatment of diseases with
high unmet medical need. Products arising from this initiative share
several key characteristics including: a genetically defined target and
disease; the potential to have a major impact in a high unmet need
population; the ability to leverage the existing Alnylam RNAi delivery
platform; the opportunity to monitor an early biomarker in Phase I
clinical trials for human proof of concept; and the existence of
clinically relevant endpoints for the filing of a new drug application
(NDA) with a focused patient database and possible accelerated paths for
commercialization. By the end of 2015, the company expects to have five
such RNAi therapeutic programs in clinical development, including
programs in advanced stages, on its own or with a partner. The “Alnylam
5x15” programs include: ALN-TTR02, an intravenously delivered RNAi
therapeutic targeting transthyretin (TTR) for the treatment of
TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic
polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi
therapeutic targeting TTR for the treatment of ATTR in patients with
familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic
targeting antithrombin (AT) for the treatment of hemophilia and rare
bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting
aminolevulinate synthase-1 (ALAS-1) for the treatment of acute
intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting
PCSK9 for the treatment of hypercholesterolemia; ALN-TMP, an RNAi
therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and
iron-overload disorders; ALN-AAT, an RNAi therapeutic targeting
alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver
disease; and ALN-CC5, an RNAi therapeutic targeting the C5 component of
the complement pathway for the treatment of complement-mediated
diseases, amongst other programs. Alnylam intends to focus on developing
and commercializing certain programs from this product strategy itself
in North and South America, Europe, and other parts of the world; these
include ALN-TTR, ALN-AT3, and ALN-AS1; the company will seek global
development and commercial alliances for other programs.

Alnylam Forward-Looking Statements

Various statements in this press release concerning Alnylam's future
expectations, plans and prospects, including without limitation,
Alnylam's expectations regarding its “Alnylam 5x15” product strategy,
Alnylam's views with respect to the potential for RNAi therapeutics,
including ALN-TTRsc, its expectations regarding the reporting of data
from its ALN-TTRsc clinical trials, its expectations with respect to the
timing and success of its clinical trials for ALN-TTRsc, and its
expectations regarding the potential market opportunity for ALN-TTRsc,
constitute forward-looking statements for the purposes of the safe
harbor provisions under The Private Securities Litigation Reform Act of
1995. Actual results may differ materially from those indicated by these
forward-looking statements as a result of various important factors,
including, without limitation, Alnylam's ability to discover and develop
novel drug candidates and delivery approaches, successfully demonstrate
the efficacy and safety of its drug candidates, including ALN-TTRsc, the
pre-clinical and clinical results for its product candidates, which may
not support further development of product candidates, actions of
regulatory agencies, which may affect the initiation, timing and
progress of clinical trials, obtaining, maintaining and protecting
intellectual property, Alnylam's ability to enforce its patents against
infringers and defend its patent portfolio against challenges from third
parties, obtaining regulatory approval for products, competition from
others using technology similar to Alnylam's and others developing
products for similar uses, Alnylam's ability to obtain additional
funding to support its business activities and establish and maintain
strategic business alliances and new business initiatives, Alnylam's
dependence on third parties for development, manufacture, marketing,
sales and distribution of products, the outcome of litigation, and
unexpected expenditures, as well as those risks more fully discussed in
the “Risk Factors” filed with Alnylam's current report on Form 10-Q
filed with the Securities and Exchange Commission (SEC) on May 7, 2013
and in other filings that Alnylam makes with the SEC. In addition, any
forward-looking statements represent Alnylam's views only as of today
and should not be relied upon as representing its views as of any
subsequent date. Alnylam explicitly disclaims any obligation to update
any forward-looking statements.

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